The Experts below are selected from a list of 153 Experts worldwide ranked by ideXlab platform

Richard J. Martin - One of the best experts on this subject based on the ideXlab platform.

  • Investigation of Acetylcholine Receptor Diversity in a Nematode Parasite Leads to Characterization of Tribendimidine- and Derquantel-Sensitive nAChRs
    2016
    Co-Authors: Samuel K Buxton, Melanie Abongwa, Alan P. Robertson, Elise Courtot, Cédric Neveu, Claude Charvet, Jacques Cortet, Nicolas Peineau, Jacques Cabaret, Richard J. Martin
    Abstract:

    Nicotinic acetylcholine receptors (nAChRs) of parasitic nematodes are required for body movement and are targets of important ‘‘classical’ ’ anthelmintics like levamisole and pyrantel, as well as ‘‘novel’ ’ anthelmintics like tribendimidine and Derquantel. Four biophysical subtypes of nAChR have been observed electrophysiologically in body muscle of the nematode parasite Oesophagostomum dentatum, but their molecular basis was not understood. Additionally, loss of one of these subtypes (G 35 pS) was found to be associated with levamisole resistance. In the present study, we identified and expressed in Xenopus oocytes, four O. dentatum nAChR subunit genes, Ode-unc-38, Ode-unc-63, Ode-unc-29 and Ode-acr-8, to explore the origin of the receptor diversity. When different combinations of subunits were injected in Xenopus oocytes, we reconstituted and characterized four pharmacologically different types of nAChRs with different sensitivities to the cholinergic anthelmintics. Moreover, we demonstrate that the receptor diversity may be affected by the stoichiometric arrangement of the subunits. We show, for the first time, different combinations of subunits from a parasitic nematode that make up receptors sensitive to tribendimidine and Derquantel. In addition, we report that the recombinant levamisole-sensitive receptor made up of Ode-UNC-29, Ode-UNC-63, Ode-UNC-38 and Ode-ACR-8 subunits has the same single-channel conductance, 35 pS and 2.4 ms mean open-time properties, as the levamisole-AChR (G35) subtype previously identified in vivo. These data highlight the flexible arrangements of the receptor subunits and their effects on sensitivity an

  • RESEARCH ARTICLE Curiouser and Curiouser: The Macrocyclic Lactone, Abamectin, Is also a Potent Inhibitor of Pyrantel/Tribendimidine Nicotinic Acetylcholine Receptors of Gastro-Intestinal Worms
    2016
    Co-Authors: Melanie Abongwa, Samuel K Buxton, Alan P. Robertson, Richard J. Martin
    Abstract:

    Nematode parasites may be controlled with drugs, but their regular application has given rise to concerns about the development of resistance. Drug combinations may be more effective than single drugs and delay the onset of resistance. A combination of the nicotinic antagonist, Derquantel, and the macrocyclic lactone, abamectin, has been found to have synergistic anthelmintic effects against gastro-intestinal nematode parasites. We have observed in previous contraction and electrophysiological experiments that Derquantel is a potent selective antagonist of nematode parasite muscle nicotinic receptors; and that aba-mectin is an inhibitor of the same nicotinic receptors. To explore these inhibitory effects fur-ther, we expressed muscle nicotinic receptors of the nodular worm,Oesophagostomum dentatum (Ode-UNC-29:Ode-UNC-63:Ode-UNC-38), in Xenopus oocytes under voltage-clamp and tested effects of abamectin on pyrantel and acetylcholine responses. The recep-tors were antagonized by 0.03 μM abamectin in a non-competitive manner (reduced Rmax, no change in EC50). This antagonism increased when abamectin was increased to 0.1 μM. However, when we increased the concentration of abamectin further to 0.3 μM, 1 μM o

  • Curiouser and Curiouser: The Macrocyclic Lactone, Abamectin, Is also a Potent Inhibitor of Pyrantel/Tribendimidine Nicotinic Acetylcholine Receptors of Gastro-Intestinal Worms.
    PloS one, 2016
    Co-Authors: Melanie Abongwa, Samuel K Buxton, Alan P. Robertson, Richard J. Martin
    Abstract:

    Nematode parasites may be controlled with drugs, but their regular application has given rise to concerns about the development of resistance. Drug combinations may be more effective than single drugs and delay the onset of resistance. A combination of the nicotinic antagonist, Derquantel, and the macrocyclic lactone, abamectin, has been found to have synergistic anthelmintic effects against gastro-intestinal nematode parasites. We have observed in previous contraction and electrophysiological experiments that Derquantel is a potent selective antagonist of nematode parasite muscle nicotinic receptors; and that abamectin is an inhibitor of the same nicotinic receptors. To explore these inhibitory effects further, we expressed muscle nicotinic receptors of the nodular worm, Oesophagostomum dentatum (Ode-UNC-29:Ode-UNC-63:Ode-UNC-38), in Xenopus oocytes under voltage-clamp and tested effects of abamectin on pyrantel and acetylcholine responses. The receptors were antagonized by 0.03 μM abamectin in a non-competitive manner (reduced Rmax, no change in EC50). This antagonism increased when abamectin was increased to 0.1 μM. However, when we increased the concentration of abamectin further to 0.3 μM, 1 μM or 10 μM, we found that the antagonism decreased and was less than with 0.1 μM abamectin. The bi-phasic effects of abamectin suggest that abamectin acts at two allosteric sites: one high affinity negative allosteric (NAM) site causing antagonism, and another lower affinity positive allosteric (PAM) site causing a reduction in antagonism. We also tested the effects of 0.1 μM Derquantel alone and in combination with 0.3 μM abamectin. We found that Derquantel on these receptors, like abamectin, acted as a non-competitive antagonist, and that the combination of Derquantel and abamectin produced greater inhibition. These observations confirm the antagonistic effects of abamectin on nematode nicotinic receptors in addition to GluCl effects, and illustrate more complex effects of macrocyclic lactones that may be exploited in combinations with other anthelmintics.

  • curiouser and curiouser the macrocyclic lactone abamectin is also a potent inhibitor of pyrantel tribendimidine nicotinic acetylcholine receptors of gastro intestinal worms
    PLOS ONE, 2016
    Co-Authors: Melanie Abongwa, Samuel K Buxton, Alan P. Robertson, Richard J. Martin
    Abstract:

    Nematode parasites may be controlled with drugs, but their regular application has given rise to concerns about the development of resistance. Drug combinations may be more effective than single drugs and delay the onset of resistance. A combination of the nicotinic antagonist, Derquantel, and the macrocyclic lactone, abamectin, has been found to have synergistic anthelmintic effects against gastro-intestinal nematode parasites. We have observed in previous contraction and electrophysiological experiments that Derquantel is a potent selective antagonist of nematode parasite muscle nicotinic receptors; and that abamectin is an inhibitor of the same nicotinic receptors. To explore these inhibitory effects further, we expressed muscle nicotinic receptors of the nodular worm, Oesophagostomum dentatum (Ode-UNC-29:Ode-UNC-63:Ode-UNC-38), in Xenopus oocytes under voltage-clamp and tested effects of abamectin on pyrantel and acetylcholine responses. The receptors were antagonized by 0.03 μM abamectin in a non-competitive manner (reduced Rmax, no change in EC50). This antagonism increased when abamectin was increased to 0.1 μM. However, when we increased the concentration of abamectin further to 0.3 μM, 1 μM or 10 μM, we found that the antagonism decreased and was less than with 0.1 μM abamectin. The bi-phasic effects of abamectin suggest that abamectin acts at two allosteric sites: one high affinity negative allosteric (NAM) site causing antagonism, and another lower affinity positive allosteric (PAM) site causing a reduction in antagonism. We also tested the effects of 0.1 μM Derquantel alone and in combination with 0.3 μM abamectin. We found that Derquantel on these receptors, like abamectin, acted as a non-competitive antagonist, and that the combination of Derquantel and abamectin produced greater inhibition. These observations confirm the antagonistic effects of abamectin on nematode nicotinic receptors in addition to GluCl effects, and illustrate more complex effects of macrocyclic lactones that may be exploited in combinations with other anthelmintics.

  • Effects of 0.1 μM Derquantel alone, 0.3 μM abamectin alone, and Derquantel and abamectin combination (0.1 μM Derquantel + 0.3 μM abamectin) on the pyrantel concentration-response plots.
    2016
    Co-Authors: Melanie Abongwa, Samuel K Buxton, Alan P. Robertson, Richard J. Martin
    Abstract:

    A: Representative trace (inward currents from oocytes expressing Ode-UNC-29:Ode-UNC-63:Ode-UNC-38) of the 10 seconds application of the control 100 μM acetylcholine, followed by a 10 minutes application of 0.3 μM abamectin and finally, a 10 seconds application of different pyrantel concentrations in the continued presence of abamectin. B: Representative trace (inward currents from oocytes expressing Ode-UNC-29:Ode-UNC-63:Ode-UNC-38) of the 10 seconds application of the control 100 μM acetylcholine, followed by a 10 minutes application of Derquantel and abamectin combination and finally, a 10 seconds application of different pyrantel concentrations in the continued presence of the Derquantel and abamectin combination. C: Concentration-response plots for pyrantel in the absence (n = 6, red) and presence of 0.1 μM Derquantel (n = 4, light purple); 0.3 μM abamectin (n = 5, dark green); 0.1 μM Derquantel + 0.3 μM abamectin combination (n = 6, olive green). Results were normalized to 100 μM acetylcholine current responses and expressed as mean ± S.E.M. Inhibition with 0.1 μM Derquantel + 0.3 μM abamectin combination was greater than that with 0.1 μM Derquantel alone and 0.3 μM abamectin alone. The calculated additive effect for the combination of Derquantel and abamectin (broken black) was not statistically different (p > 0.05, paired two-tailed student t-test) from the observed additive effect for the combination of Derquantel and abamectin (olive green). D: Bar chart showing the mean ± S.E.M of the maximum current responses (Rmax) for 0.1 μM Derquantel (n = 4, light purple); 0.3 μM abamectin (n = 5, dark green); 0.1 μM Derquantel + 0.3 μM abamectin combination (n = 6, olive green). Rmax for the combination of 0.1 μM Derquantel + 0.3 μM abamectin was significantly smaller than Rmax for 0.1 μM Derquantel alone and for 0.3 μM abamectin alone. * p < 0.05 and *** p < 0.001, unpaired two-tailed student t-test.

Melanie Abongwa - One of the best experts on this subject based on the ideXlab platform.

  • Investigation of Acetylcholine Receptor Diversity in a Nematode Parasite Leads to Characterization of Tribendimidine- and Derquantel-Sensitive nAChRs
    2016
    Co-Authors: Samuel K Buxton, Melanie Abongwa, Alan P. Robertson, Elise Courtot, Cédric Neveu, Claude Charvet, Jacques Cortet, Nicolas Peineau, Jacques Cabaret, Richard J. Martin
    Abstract:

    Nicotinic acetylcholine receptors (nAChRs) of parasitic nematodes are required for body movement and are targets of important ‘‘classical’ ’ anthelmintics like levamisole and pyrantel, as well as ‘‘novel’ ’ anthelmintics like tribendimidine and Derquantel. Four biophysical subtypes of nAChR have been observed electrophysiologically in body muscle of the nematode parasite Oesophagostomum dentatum, but their molecular basis was not understood. Additionally, loss of one of these subtypes (G 35 pS) was found to be associated with levamisole resistance. In the present study, we identified and expressed in Xenopus oocytes, four O. dentatum nAChR subunit genes, Ode-unc-38, Ode-unc-63, Ode-unc-29 and Ode-acr-8, to explore the origin of the receptor diversity. When different combinations of subunits were injected in Xenopus oocytes, we reconstituted and characterized four pharmacologically different types of nAChRs with different sensitivities to the cholinergic anthelmintics. Moreover, we demonstrate that the receptor diversity may be affected by the stoichiometric arrangement of the subunits. We show, for the first time, different combinations of subunits from a parasitic nematode that make up receptors sensitive to tribendimidine and Derquantel. In addition, we report that the recombinant levamisole-sensitive receptor made up of Ode-UNC-29, Ode-UNC-63, Ode-UNC-38 and Ode-ACR-8 subunits has the same single-channel conductance, 35 pS and 2.4 ms mean open-time properties, as the levamisole-AChR (G35) subtype previously identified in vivo. These data highlight the flexible arrangements of the receptor subunits and their effects on sensitivity an

  • RESEARCH ARTICLE Curiouser and Curiouser: The Macrocyclic Lactone, Abamectin, Is also a Potent Inhibitor of Pyrantel/Tribendimidine Nicotinic Acetylcholine Receptors of Gastro-Intestinal Worms
    2016
    Co-Authors: Melanie Abongwa, Samuel K Buxton, Alan P. Robertson, Richard J. Martin
    Abstract:

    Nematode parasites may be controlled with drugs, but their regular application has given rise to concerns about the development of resistance. Drug combinations may be more effective than single drugs and delay the onset of resistance. A combination of the nicotinic antagonist, Derquantel, and the macrocyclic lactone, abamectin, has been found to have synergistic anthelmintic effects against gastro-intestinal nematode parasites. We have observed in previous contraction and electrophysiological experiments that Derquantel is a potent selective antagonist of nematode parasite muscle nicotinic receptors; and that aba-mectin is an inhibitor of the same nicotinic receptors. To explore these inhibitory effects fur-ther, we expressed muscle nicotinic receptors of the nodular worm,Oesophagostomum dentatum (Ode-UNC-29:Ode-UNC-63:Ode-UNC-38), in Xenopus oocytes under voltage-clamp and tested effects of abamectin on pyrantel and acetylcholine responses. The recep-tors were antagonized by 0.03 μM abamectin in a non-competitive manner (reduced Rmax, no change in EC50). This antagonism increased when abamectin was increased to 0.1 μM. However, when we increased the concentration of abamectin further to 0.3 μM, 1 μM o

  • curiouser and curiouser the macrocyclic lactone abamectin is also a potent inhibitor of pyrantel tribendimidine nicotinic acetylcholine receptors of gastro intestinal worms
    PLOS ONE, 2016
    Co-Authors: Melanie Abongwa, Samuel K Buxton, Alan P. Robertson, Richard J. Martin
    Abstract:

    Nematode parasites may be controlled with drugs, but their regular application has given rise to concerns about the development of resistance. Drug combinations may be more effective than single drugs and delay the onset of resistance. A combination of the nicotinic antagonist, Derquantel, and the macrocyclic lactone, abamectin, has been found to have synergistic anthelmintic effects against gastro-intestinal nematode parasites. We have observed in previous contraction and electrophysiological experiments that Derquantel is a potent selective antagonist of nematode parasite muscle nicotinic receptors; and that abamectin is an inhibitor of the same nicotinic receptors. To explore these inhibitory effects further, we expressed muscle nicotinic receptors of the nodular worm, Oesophagostomum dentatum (Ode-UNC-29:Ode-UNC-63:Ode-UNC-38), in Xenopus oocytes under voltage-clamp and tested effects of abamectin on pyrantel and acetylcholine responses. The receptors were antagonized by 0.03 μM abamectin in a non-competitive manner (reduced Rmax, no change in EC50). This antagonism increased when abamectin was increased to 0.1 μM. However, when we increased the concentration of abamectin further to 0.3 μM, 1 μM or 10 μM, we found that the antagonism decreased and was less than with 0.1 μM abamectin. The bi-phasic effects of abamectin suggest that abamectin acts at two allosteric sites: one high affinity negative allosteric (NAM) site causing antagonism, and another lower affinity positive allosteric (PAM) site causing a reduction in antagonism. We also tested the effects of 0.1 μM Derquantel alone and in combination with 0.3 μM abamectin. We found that Derquantel on these receptors, like abamectin, acted as a non-competitive antagonist, and that the combination of Derquantel and abamectin produced greater inhibition. These observations confirm the antagonistic effects of abamectin on nematode nicotinic receptors in addition to GluCl effects, and illustrate more complex effects of macrocyclic lactones that may be exploited in combinations with other anthelmintics.

  • Curiouser and Curiouser: The Macrocyclic Lactone, Abamectin, Is also a Potent Inhibitor of Pyrantel/Tribendimidine Nicotinic Acetylcholine Receptors of Gastro-Intestinal Worms.
    PloS one, 2016
    Co-Authors: Melanie Abongwa, Samuel K Buxton, Alan P. Robertson, Richard J. Martin
    Abstract:

    Nematode parasites may be controlled with drugs, but their regular application has given rise to concerns about the development of resistance. Drug combinations may be more effective than single drugs and delay the onset of resistance. A combination of the nicotinic antagonist, Derquantel, and the macrocyclic lactone, abamectin, has been found to have synergistic anthelmintic effects against gastro-intestinal nematode parasites. We have observed in previous contraction and electrophysiological experiments that Derquantel is a potent selective antagonist of nematode parasite muscle nicotinic receptors; and that abamectin is an inhibitor of the same nicotinic receptors. To explore these inhibitory effects further, we expressed muscle nicotinic receptors of the nodular worm, Oesophagostomum dentatum (Ode-UNC-29:Ode-UNC-63:Ode-UNC-38), in Xenopus oocytes under voltage-clamp and tested effects of abamectin on pyrantel and acetylcholine responses. The receptors were antagonized by 0.03 μM abamectin in a non-competitive manner (reduced Rmax, no change in EC50). This antagonism increased when abamectin was increased to 0.1 μM. However, when we increased the concentration of abamectin further to 0.3 μM, 1 μM or 10 μM, we found that the antagonism decreased and was less than with 0.1 μM abamectin. The bi-phasic effects of abamectin suggest that abamectin acts at two allosteric sites: one high affinity negative allosteric (NAM) site causing antagonism, and another lower affinity positive allosteric (PAM) site causing a reduction in antagonism. We also tested the effects of 0.1 μM Derquantel alone and in combination with 0.3 μM abamectin. We found that Derquantel on these receptors, like abamectin, acted as a non-competitive antagonist, and that the combination of Derquantel and abamectin produced greater inhibition. These observations confirm the antagonistic effects of abamectin on nematode nicotinic receptors in addition to GluCl effects, and illustrate more complex effects of macrocyclic lactones that may be exploited in combinations with other anthelmintics.

  • Effects of 0.1 μM Derquantel alone, 0.3 μM abamectin alone, and Derquantel and abamectin combination (0.1 μM Derquantel + 0.3 μM abamectin) on the pyrantel concentration-response plots.
    2016
    Co-Authors: Melanie Abongwa, Samuel K Buxton, Alan P. Robertson, Richard J. Martin
    Abstract:

    A: Representative trace (inward currents from oocytes expressing Ode-UNC-29:Ode-UNC-63:Ode-UNC-38) of the 10 seconds application of the control 100 μM acetylcholine, followed by a 10 minutes application of 0.3 μM abamectin and finally, a 10 seconds application of different pyrantel concentrations in the continued presence of abamectin. B: Representative trace (inward currents from oocytes expressing Ode-UNC-29:Ode-UNC-63:Ode-UNC-38) of the 10 seconds application of the control 100 μM acetylcholine, followed by a 10 minutes application of Derquantel and abamectin combination and finally, a 10 seconds application of different pyrantel concentrations in the continued presence of the Derquantel and abamectin combination. C: Concentration-response plots for pyrantel in the absence (n = 6, red) and presence of 0.1 μM Derquantel (n = 4, light purple); 0.3 μM abamectin (n = 5, dark green); 0.1 μM Derquantel + 0.3 μM abamectin combination (n = 6, olive green). Results were normalized to 100 μM acetylcholine current responses and expressed as mean ± S.E.M. Inhibition with 0.1 μM Derquantel + 0.3 μM abamectin combination was greater than that with 0.1 μM Derquantel alone and 0.3 μM abamectin alone. The calculated additive effect for the combination of Derquantel and abamectin (broken black) was not statistically different (p > 0.05, paired two-tailed student t-test) from the observed additive effect for the combination of Derquantel and abamectin (olive green). D: Bar chart showing the mean ± S.E.M of the maximum current responses (Rmax) for 0.1 μM Derquantel (n = 4, light purple); 0.3 μM abamectin (n = 5, dark green); 0.1 μM Derquantel + 0.3 μM abamectin combination (n = 6, olive green). Rmax for the combination of 0.1 μM Derquantel + 0.3 μM abamectin was significantly smaller than Rmax for 0.1 μM Derquantel alone and for 0.3 μM abamectin alone. * p < 0.05 and *** p < 0.001, unpaired two-tailed student t-test.

Alan P. Robertson - One of the best experts on this subject based on the ideXlab platform.

  • Investigation of Acetylcholine Receptor Diversity in a Nematode Parasite Leads to Characterization of Tribendimidine- and Derquantel-Sensitive nAChRs
    2016
    Co-Authors: Samuel K Buxton, Melanie Abongwa, Alan P. Robertson, Elise Courtot, Cédric Neveu, Claude Charvet, Jacques Cortet, Nicolas Peineau, Jacques Cabaret, Richard J. Martin
    Abstract:

    Nicotinic acetylcholine receptors (nAChRs) of parasitic nematodes are required for body movement and are targets of important ‘‘classical’ ’ anthelmintics like levamisole and pyrantel, as well as ‘‘novel’ ’ anthelmintics like tribendimidine and Derquantel. Four biophysical subtypes of nAChR have been observed electrophysiologically in body muscle of the nematode parasite Oesophagostomum dentatum, but their molecular basis was not understood. Additionally, loss of one of these subtypes (G 35 pS) was found to be associated with levamisole resistance. In the present study, we identified and expressed in Xenopus oocytes, four O. dentatum nAChR subunit genes, Ode-unc-38, Ode-unc-63, Ode-unc-29 and Ode-acr-8, to explore the origin of the receptor diversity. When different combinations of subunits were injected in Xenopus oocytes, we reconstituted and characterized four pharmacologically different types of nAChRs with different sensitivities to the cholinergic anthelmintics. Moreover, we demonstrate that the receptor diversity may be affected by the stoichiometric arrangement of the subunits. We show, for the first time, different combinations of subunits from a parasitic nematode that make up receptors sensitive to tribendimidine and Derquantel. In addition, we report that the recombinant levamisole-sensitive receptor made up of Ode-UNC-29, Ode-UNC-63, Ode-UNC-38 and Ode-ACR-8 subunits has the same single-channel conductance, 35 pS and 2.4 ms mean open-time properties, as the levamisole-AChR (G35) subtype previously identified in vivo. These data highlight the flexible arrangements of the receptor subunits and their effects on sensitivity an

  • RESEARCH ARTICLE Curiouser and Curiouser: The Macrocyclic Lactone, Abamectin, Is also a Potent Inhibitor of Pyrantel/Tribendimidine Nicotinic Acetylcholine Receptors of Gastro-Intestinal Worms
    2016
    Co-Authors: Melanie Abongwa, Samuel K Buxton, Alan P. Robertson, Richard J. Martin
    Abstract:

    Nematode parasites may be controlled with drugs, but their regular application has given rise to concerns about the development of resistance. Drug combinations may be more effective than single drugs and delay the onset of resistance. A combination of the nicotinic antagonist, Derquantel, and the macrocyclic lactone, abamectin, has been found to have synergistic anthelmintic effects against gastro-intestinal nematode parasites. We have observed in previous contraction and electrophysiological experiments that Derquantel is a potent selective antagonist of nematode parasite muscle nicotinic receptors; and that aba-mectin is an inhibitor of the same nicotinic receptors. To explore these inhibitory effects fur-ther, we expressed muscle nicotinic receptors of the nodular worm,Oesophagostomum dentatum (Ode-UNC-29:Ode-UNC-63:Ode-UNC-38), in Xenopus oocytes under voltage-clamp and tested effects of abamectin on pyrantel and acetylcholine responses. The recep-tors were antagonized by 0.03 μM abamectin in a non-competitive manner (reduced Rmax, no change in EC50). This antagonism increased when abamectin was increased to 0.1 μM. However, when we increased the concentration of abamectin further to 0.3 μM, 1 μM o

  • Curiouser and Curiouser: The Macrocyclic Lactone, Abamectin, Is also a Potent Inhibitor of Pyrantel/Tribendimidine Nicotinic Acetylcholine Receptors of Gastro-Intestinal Worms.
    PloS one, 2016
    Co-Authors: Melanie Abongwa, Samuel K Buxton, Alan P. Robertson, Richard J. Martin
    Abstract:

    Nematode parasites may be controlled with drugs, but their regular application has given rise to concerns about the development of resistance. Drug combinations may be more effective than single drugs and delay the onset of resistance. A combination of the nicotinic antagonist, Derquantel, and the macrocyclic lactone, abamectin, has been found to have synergistic anthelmintic effects against gastro-intestinal nematode parasites. We have observed in previous contraction and electrophysiological experiments that Derquantel is a potent selective antagonist of nematode parasite muscle nicotinic receptors; and that abamectin is an inhibitor of the same nicotinic receptors. To explore these inhibitory effects further, we expressed muscle nicotinic receptors of the nodular worm, Oesophagostomum dentatum (Ode-UNC-29:Ode-UNC-63:Ode-UNC-38), in Xenopus oocytes under voltage-clamp and tested effects of abamectin on pyrantel and acetylcholine responses. The receptors were antagonized by 0.03 μM abamectin in a non-competitive manner (reduced Rmax, no change in EC50). This antagonism increased when abamectin was increased to 0.1 μM. However, when we increased the concentration of abamectin further to 0.3 μM, 1 μM or 10 μM, we found that the antagonism decreased and was less than with 0.1 μM abamectin. The bi-phasic effects of abamectin suggest that abamectin acts at two allosteric sites: one high affinity negative allosteric (NAM) site causing antagonism, and another lower affinity positive allosteric (PAM) site causing a reduction in antagonism. We also tested the effects of 0.1 μM Derquantel alone and in combination with 0.3 μM abamectin. We found that Derquantel on these receptors, like abamectin, acted as a non-competitive antagonist, and that the combination of Derquantel and abamectin produced greater inhibition. These observations confirm the antagonistic effects of abamectin on nematode nicotinic receptors in addition to GluCl effects, and illustrate more complex effects of macrocyclic lactones that may be exploited in combinations with other anthelmintics.

  • curiouser and curiouser the macrocyclic lactone abamectin is also a potent inhibitor of pyrantel tribendimidine nicotinic acetylcholine receptors of gastro intestinal worms
    PLOS ONE, 2016
    Co-Authors: Melanie Abongwa, Samuel K Buxton, Alan P. Robertson, Richard J. Martin
    Abstract:

    Nematode parasites may be controlled with drugs, but their regular application has given rise to concerns about the development of resistance. Drug combinations may be more effective than single drugs and delay the onset of resistance. A combination of the nicotinic antagonist, Derquantel, and the macrocyclic lactone, abamectin, has been found to have synergistic anthelmintic effects against gastro-intestinal nematode parasites. We have observed in previous contraction and electrophysiological experiments that Derquantel is a potent selective antagonist of nematode parasite muscle nicotinic receptors; and that abamectin is an inhibitor of the same nicotinic receptors. To explore these inhibitory effects further, we expressed muscle nicotinic receptors of the nodular worm, Oesophagostomum dentatum (Ode-UNC-29:Ode-UNC-63:Ode-UNC-38), in Xenopus oocytes under voltage-clamp and tested effects of abamectin on pyrantel and acetylcholine responses. The receptors were antagonized by 0.03 μM abamectin in a non-competitive manner (reduced Rmax, no change in EC50). This antagonism increased when abamectin was increased to 0.1 μM. However, when we increased the concentration of abamectin further to 0.3 μM, 1 μM or 10 μM, we found that the antagonism decreased and was less than with 0.1 μM abamectin. The bi-phasic effects of abamectin suggest that abamectin acts at two allosteric sites: one high affinity negative allosteric (NAM) site causing antagonism, and another lower affinity positive allosteric (PAM) site causing a reduction in antagonism. We also tested the effects of 0.1 μM Derquantel alone and in combination with 0.3 μM abamectin. We found that Derquantel on these receptors, like abamectin, acted as a non-competitive antagonist, and that the combination of Derquantel and abamectin produced greater inhibition. These observations confirm the antagonistic effects of abamectin on nematode nicotinic receptors in addition to GluCl effects, and illustrate more complex effects of macrocyclic lactones that may be exploited in combinations with other anthelmintics.

  • Effects of 0.1 μM Derquantel alone, 0.3 μM abamectin alone, and Derquantel and abamectin combination (0.1 μM Derquantel + 0.3 μM abamectin) on the pyrantel concentration-response plots.
    2016
    Co-Authors: Melanie Abongwa, Samuel K Buxton, Alan P. Robertson, Richard J. Martin
    Abstract:

    A: Representative trace (inward currents from oocytes expressing Ode-UNC-29:Ode-UNC-63:Ode-UNC-38) of the 10 seconds application of the control 100 μM acetylcholine, followed by a 10 minutes application of 0.3 μM abamectin and finally, a 10 seconds application of different pyrantel concentrations in the continued presence of abamectin. B: Representative trace (inward currents from oocytes expressing Ode-UNC-29:Ode-UNC-63:Ode-UNC-38) of the 10 seconds application of the control 100 μM acetylcholine, followed by a 10 minutes application of Derquantel and abamectin combination and finally, a 10 seconds application of different pyrantel concentrations in the continued presence of the Derquantel and abamectin combination. C: Concentration-response plots for pyrantel in the absence (n = 6, red) and presence of 0.1 μM Derquantel (n = 4, light purple); 0.3 μM abamectin (n = 5, dark green); 0.1 μM Derquantel + 0.3 μM abamectin combination (n = 6, olive green). Results were normalized to 100 μM acetylcholine current responses and expressed as mean ± S.E.M. Inhibition with 0.1 μM Derquantel + 0.3 μM abamectin combination was greater than that with 0.1 μM Derquantel alone and 0.3 μM abamectin alone. The calculated additive effect for the combination of Derquantel and abamectin (broken black) was not statistically different (p > 0.05, paired two-tailed student t-test) from the observed additive effect for the combination of Derquantel and abamectin (olive green). D: Bar chart showing the mean ± S.E.M of the maximum current responses (Rmax) for 0.1 μM Derquantel (n = 4, light purple); 0.3 μM abamectin (n = 5, dark green); 0.1 μM Derquantel + 0.3 μM abamectin combination (n = 6, olive green). Rmax for the combination of 0.1 μM Derquantel + 0.3 μM abamectin was significantly smaller than Rmax for 0.1 μM Derquantel alone and for 0.3 μM abamectin alone. * p < 0.05 and *** p < 0.001, unpaired two-tailed student t-test.

Anziani, Oscar Sergio - One of the best experts on this subject based on the ideXlab platform.

  • Eficacia reducida de Derquantel y abamectina en ovinos y caprinos con Haemonchus sp resistentes a lactonas macrocíclicas
    'Universidad Nacional del Nordeste', 2018
    Co-Authors: Cerutti Julieta, Cooper, Laura G., Torrents Jorgelina, Suarez Archilla, Guillermo Alejandro, Anziani, Oscar Sergio
    Abstract:

    Se presentan las observaciones efectuadas sobre la actividad de una combinación antihelmíntica conteniendo un nueva droga, el Derquantel (spiroindoles) adicionada con abamectina (lactonas macrocíclicas) en ovinos y caprinos naturalmente parasitados por Haemonchus sp. En el conteo de huevos, la eficacia de la combinación mostró porcentajes de reducción variables y dependientes de los estadios parasitarios intervinientes al momento del tratamiento y al status previo de resistencia a las lactonas macrocíclicas. Se observó una eficacia alta (mayor al 99%) frente a la oviposición de estadios maduros de Haemonchus sp o cuando los antecedentes de las poblaciones parasitarias indicaban resistencia no marcada a las lactonas macrocíclicas. Por el contrario, eficacias inferiores (76 al 83%) se observaron cuando las poblaciones de este parásito mostraban resistencia severa a las lactonas macrocíclicas y los estadios inmaduros constituían la mayor parte de la población parasitaria al momento del tratamiento. Las combinaciones antihelmínticas tienen un interesante potencial de uso frente a poblaciones parasitarias de Haemonchus sp resistentes a los antihelmínticos, pero las presentes observaciones enfatizan la necesidad de evaluar a nivel de cada establecimiento la actividad de todos los antiparasitarios, sean estos formulados con viejas o nuevas drogas, si se pretende instaurar programas racionales para el control de estos nematodesA field study was carried out to determine the activity of an anthelmintic combination of Derquantel (spiroindoles) plus abamectin (macrocyclic lactones) against Haemonchus sp in sheeps and goats. The clinical efficacy of the combination showed variable egg count reduction percentage dependent on the parasitic stages involved at the time of treatment and the previous status of resistance to the macrocyclic lactones. High efficacy (greater than 99%) was observed against oviposition of mature Haemonchus sp stages or when background of parasitic populations indicated moderate resistance to macrocyclic lactones. In contrast, lower efficiencies (76-83%) were observed when populations of this parasite showed severe resistance to macrocyclic lactones and immature stages constituted the majority of the parasitic population at time of treatment. Anthelmintic combinations could have an interesting potential for prevent o manage the nematode resistance in small ruminants, but the present observations emphasize the need to evaluate at the level of each establishment the activity of all anthelmintic drenches formulated with new or old drugsEEA RafaelaFil: Cerutti, Julieta. Universidad Católica de Córdoba. Facultad Ciencias Agropecuarias; ArgentinaFil: Cooper, Laura G. Universidad Católica de Córdoba. Facultad Ciencias Agropecuarias; ArgentinaFil: Torrents, Jorgelina. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Rafaela; ArgentinaFil: Suarez Archilla, Guillermo Alejandro. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Rafaela; ArgentinaFil: Anziani, Oscar Sergio. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Rafaela; Argentina. Universidad Católica de Córdoba. Facultad de Ciencias Agropecuarias, Argentin

  • Monepatel y control de Haemonchus contortus en ovinos. Evaluación de la eficacia luego de cuatro años de uso en condiciones de refugio reducido
    'Universidad Nacional del Litoral', 2015
    Co-Authors: Torrents Jorgelina, Suarez Archilla, Guillermo Alejandro, Anziani, Oscar Sergio
    Abstract:

    La resistencia de los nematodes ovinos a los antihelmínticos está generalizada en el centro-norte de la Argentina y la mayor preocupación actual es el aumento y dispersión de Haemonchus contortus portando alelos con resistencia múltiple. Actualmente los únicos antihelmínticos de amplio espectro sin documentación de resistencia en nuestro país son el monepantel y Derquantel. Con la primera de estas drogas ya se han registrado casos de resistencia en Uruguay y Brasil por lo que es crítica la información actualizada sobre la actividad en el campo de estos antihelmínticos. Este estudio informa sobre la eficacia del monepantel luego de cuatro años de uso de esta droga sobre un aislamiento de H. contortus con resistencia múltiple (lactonas macrociclicas, closantel, levamisol y benzimidazoles) y bajo condiciones de refugio reducido. Se realizaron dos experiencias A y B (años 2014 y 2016 respectivamente) con corderos naturalmente parasitados y seleccionados en función del número de huevos por gramo de heces (≥ 250) los que fueron tratados con monepantel (2,5 mg/Kg oral). El test de reducción en el conteo de huevos post tratamiento comparando diversas fórmulas indicó que en ambas experiencias, la droga mantuvo una eficacia mayor al 97 % y que permanece activa para controlar este aislamiento de H. contortus luego de cuatro años de uso y bajo las particulares condiciones en las que se realizaron estos estudios.Resistance to anthelmintics in sheep nematode is widespread in central-northern Argentina and current major concern is the rise and spread of Haemonchus contortuscarrying multiple resistance alleles. Currently, monepantel and Derquantel are the only broad-spectrum anthelmintics without documentation of resistance in our country. With the first of these drugs, have already been registered cases of resistance in Uruguay and Brazil so it is critical update on the activity in the field of these anthelmintics. This study aims to test the effectiveness of monepantel after four years of use of this drug on an isolation of H. contortus with multiple resistance (macrocycliclactones, closantel, levamisole and benzimidazole) and under conditions of reduced refugia. Two experiences,A and B (2014 and 2016 respectively),were carried out with lambs naturally parasitized and selected by the number of eggs per gram of feces (≥ 250). In both experiences, the test of reduction in egg counts after treatment with monepantel (2.5 mgr/Kg orally) comparing various formulas indicated that the drug remained with efficacy greater than 97% after four years of use to control this isolation of H. contortusunder the field conditions of these studiesEEA RafaelaFil: Torrents, Jorgelina. Universidad Nacional del Litoral. Facultad de Ciencias Veterinarias; ArgentinaFil: Suarez Archilla, Guillermo Alejandro. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Rafaela; ArgentinaFil: Anziani, Oscar Sergio. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Rafaela; Argentina. Universidad Católica de Córdoba. Facultad de Ciencias Agropecuarias, Argentin

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  • Investigation of Acetylcholine Receptor Diversity in a Nematode Parasite Leads to Characterization of Tribendimidine- and Derquantel-Sensitive nAChRs
    2016
    Co-Authors: Samuel K Buxton, Melanie Abongwa, Alan P. Robertson, Elise Courtot, Cédric Neveu, Claude Charvet, Jacques Cortet, Nicolas Peineau, Jacques Cabaret, Richard J. Martin
    Abstract:

    Nicotinic acetylcholine receptors (nAChRs) of parasitic nematodes are required for body movement and are targets of important ‘‘classical’ ’ anthelmintics like levamisole and pyrantel, as well as ‘‘novel’ ’ anthelmintics like tribendimidine and Derquantel. Four biophysical subtypes of nAChR have been observed electrophysiologically in body muscle of the nematode parasite Oesophagostomum dentatum, but their molecular basis was not understood. Additionally, loss of one of these subtypes (G 35 pS) was found to be associated with levamisole resistance. In the present study, we identified and expressed in Xenopus oocytes, four O. dentatum nAChR subunit genes, Ode-unc-38, Ode-unc-63, Ode-unc-29 and Ode-acr-8, to explore the origin of the receptor diversity. When different combinations of subunits were injected in Xenopus oocytes, we reconstituted and characterized four pharmacologically different types of nAChRs with different sensitivities to the cholinergic anthelmintics. Moreover, we demonstrate that the receptor diversity may be affected by the stoichiometric arrangement of the subunits. We show, for the first time, different combinations of subunits from a parasitic nematode that make up receptors sensitive to tribendimidine and Derquantel. In addition, we report that the recombinant levamisole-sensitive receptor made up of Ode-UNC-29, Ode-UNC-63, Ode-UNC-38 and Ode-ACR-8 subunits has the same single-channel conductance, 35 pS and 2.4 ms mean open-time properties, as the levamisole-AChR (G35) subtype previously identified in vivo. These data highlight the flexible arrangements of the receptor subunits and their effects on sensitivity an

  • RESEARCH ARTICLE Curiouser and Curiouser: The Macrocyclic Lactone, Abamectin, Is also a Potent Inhibitor of Pyrantel/Tribendimidine Nicotinic Acetylcholine Receptors of Gastro-Intestinal Worms
    2016
    Co-Authors: Melanie Abongwa, Samuel K Buxton, Alan P. Robertson, Richard J. Martin
    Abstract:

    Nematode parasites may be controlled with drugs, but their regular application has given rise to concerns about the development of resistance. Drug combinations may be more effective than single drugs and delay the onset of resistance. A combination of the nicotinic antagonist, Derquantel, and the macrocyclic lactone, abamectin, has been found to have synergistic anthelmintic effects against gastro-intestinal nematode parasites. We have observed in previous contraction and electrophysiological experiments that Derquantel is a potent selective antagonist of nematode parasite muscle nicotinic receptors; and that aba-mectin is an inhibitor of the same nicotinic receptors. To explore these inhibitory effects fur-ther, we expressed muscle nicotinic receptors of the nodular worm,Oesophagostomum dentatum (Ode-UNC-29:Ode-UNC-63:Ode-UNC-38), in Xenopus oocytes under voltage-clamp and tested effects of abamectin on pyrantel and acetylcholine responses. The recep-tors were antagonized by 0.03 μM abamectin in a non-competitive manner (reduced Rmax, no change in EC50). This antagonism increased when abamectin was increased to 0.1 μM. However, when we increased the concentration of abamectin further to 0.3 μM, 1 μM o

  • curiouser and curiouser the macrocyclic lactone abamectin is also a potent inhibitor of pyrantel tribendimidine nicotinic acetylcholine receptors of gastro intestinal worms
    PLOS ONE, 2016
    Co-Authors: Melanie Abongwa, Samuel K Buxton, Alan P. Robertson, Richard J. Martin
    Abstract:

    Nematode parasites may be controlled with drugs, but their regular application has given rise to concerns about the development of resistance. Drug combinations may be more effective than single drugs and delay the onset of resistance. A combination of the nicotinic antagonist, Derquantel, and the macrocyclic lactone, abamectin, has been found to have synergistic anthelmintic effects against gastro-intestinal nematode parasites. We have observed in previous contraction and electrophysiological experiments that Derquantel is a potent selective antagonist of nematode parasite muscle nicotinic receptors; and that abamectin is an inhibitor of the same nicotinic receptors. To explore these inhibitory effects further, we expressed muscle nicotinic receptors of the nodular worm, Oesophagostomum dentatum (Ode-UNC-29:Ode-UNC-63:Ode-UNC-38), in Xenopus oocytes under voltage-clamp and tested effects of abamectin on pyrantel and acetylcholine responses. The receptors were antagonized by 0.03 μM abamectin in a non-competitive manner (reduced Rmax, no change in EC50). This antagonism increased when abamectin was increased to 0.1 μM. However, when we increased the concentration of abamectin further to 0.3 μM, 1 μM or 10 μM, we found that the antagonism decreased and was less than with 0.1 μM abamectin. The bi-phasic effects of abamectin suggest that abamectin acts at two allosteric sites: one high affinity negative allosteric (NAM) site causing antagonism, and another lower affinity positive allosteric (PAM) site causing a reduction in antagonism. We also tested the effects of 0.1 μM Derquantel alone and in combination with 0.3 μM abamectin. We found that Derquantel on these receptors, like abamectin, acted as a non-competitive antagonist, and that the combination of Derquantel and abamectin produced greater inhibition. These observations confirm the antagonistic effects of abamectin on nematode nicotinic receptors in addition to GluCl effects, and illustrate more complex effects of macrocyclic lactones that may be exploited in combinations with other anthelmintics.

  • Curiouser and Curiouser: The Macrocyclic Lactone, Abamectin, Is also a Potent Inhibitor of Pyrantel/Tribendimidine Nicotinic Acetylcholine Receptors of Gastro-Intestinal Worms.
    PloS one, 2016
    Co-Authors: Melanie Abongwa, Samuel K Buxton, Alan P. Robertson, Richard J. Martin
    Abstract:

    Nematode parasites may be controlled with drugs, but their regular application has given rise to concerns about the development of resistance. Drug combinations may be more effective than single drugs and delay the onset of resistance. A combination of the nicotinic antagonist, Derquantel, and the macrocyclic lactone, abamectin, has been found to have synergistic anthelmintic effects against gastro-intestinal nematode parasites. We have observed in previous contraction and electrophysiological experiments that Derquantel is a potent selective antagonist of nematode parasite muscle nicotinic receptors; and that abamectin is an inhibitor of the same nicotinic receptors. To explore these inhibitory effects further, we expressed muscle nicotinic receptors of the nodular worm, Oesophagostomum dentatum (Ode-UNC-29:Ode-UNC-63:Ode-UNC-38), in Xenopus oocytes under voltage-clamp and tested effects of abamectin on pyrantel and acetylcholine responses. The receptors were antagonized by 0.03 μM abamectin in a non-competitive manner (reduced Rmax, no change in EC50). This antagonism increased when abamectin was increased to 0.1 μM. However, when we increased the concentration of abamectin further to 0.3 μM, 1 μM or 10 μM, we found that the antagonism decreased and was less than with 0.1 μM abamectin. The bi-phasic effects of abamectin suggest that abamectin acts at two allosteric sites: one high affinity negative allosteric (NAM) site causing antagonism, and another lower affinity positive allosteric (PAM) site causing a reduction in antagonism. We also tested the effects of 0.1 μM Derquantel alone and in combination with 0.3 μM abamectin. We found that Derquantel on these receptors, like abamectin, acted as a non-competitive antagonist, and that the combination of Derquantel and abamectin produced greater inhibition. These observations confirm the antagonistic effects of abamectin on nematode nicotinic receptors in addition to GluCl effects, and illustrate more complex effects of macrocyclic lactones that may be exploited in combinations with other anthelmintics.

  • Effects of 0.1 μM Derquantel alone, 0.3 μM abamectin alone, and Derquantel and abamectin combination (0.1 μM Derquantel + 0.3 μM abamectin) on the pyrantel concentration-response plots.
    2016
    Co-Authors: Melanie Abongwa, Samuel K Buxton, Alan P. Robertson, Richard J. Martin
    Abstract:

    A: Representative trace (inward currents from oocytes expressing Ode-UNC-29:Ode-UNC-63:Ode-UNC-38) of the 10 seconds application of the control 100 μM acetylcholine, followed by a 10 minutes application of 0.3 μM abamectin and finally, a 10 seconds application of different pyrantel concentrations in the continued presence of abamectin. B: Representative trace (inward currents from oocytes expressing Ode-UNC-29:Ode-UNC-63:Ode-UNC-38) of the 10 seconds application of the control 100 μM acetylcholine, followed by a 10 minutes application of Derquantel and abamectin combination and finally, a 10 seconds application of different pyrantel concentrations in the continued presence of the Derquantel and abamectin combination. C: Concentration-response plots for pyrantel in the absence (n = 6, red) and presence of 0.1 μM Derquantel (n = 4, light purple); 0.3 μM abamectin (n = 5, dark green); 0.1 μM Derquantel + 0.3 μM abamectin combination (n = 6, olive green). Results were normalized to 100 μM acetylcholine current responses and expressed as mean ± S.E.M. Inhibition with 0.1 μM Derquantel + 0.3 μM abamectin combination was greater than that with 0.1 μM Derquantel alone and 0.3 μM abamectin alone. The calculated additive effect for the combination of Derquantel and abamectin (broken black) was not statistically different (p > 0.05, paired two-tailed student t-test) from the observed additive effect for the combination of Derquantel and abamectin (olive green). D: Bar chart showing the mean ± S.E.M of the maximum current responses (Rmax) for 0.1 μM Derquantel (n = 4, light purple); 0.3 μM abamectin (n = 5, dark green); 0.1 μM Derquantel + 0.3 μM abamectin combination (n = 6, olive green). Rmax for the combination of 0.1 μM Derquantel + 0.3 μM abamectin was significantly smaller than Rmax for 0.1 μM Derquantel alone and for 0.3 μM abamectin alone. * p < 0.05 and *** p < 0.001, unpaired two-tailed student t-test.